Fungal infectious diseases in humans and animals can be largely classified into two types depending on the position of infected tissue: systemic mycoses, and dermatomycoses. Among them, systemic mycoses include cryptococcosis, candidasis, aspergillosis, etc., which do not frequently occur in healthy persons, but frequently occur in persons with weak immunity. Cryptococcosis is caused by infection with Cryptococcus neoformans which infects all parts (including skin) of patients with low immunity, such as AIDS patients, and particularly, infects the brain and meninges to cause meningitis, brain abscess and brain tumor. Candidasis is mycosis caused by Candida albicans, and was first isolated from an oral thrush patient. Moreover, Candidasis causes vaginitis in women and causes diaper rash in infants.
In recent years, with the increase in the number of immunocompromised patients by anticancer chemotherapy or administration of immunosuppressants after organ transplantation or in the number of AIDS patients, the incidence of systemic fungal infections has greatly increased, and the severity thereof also has increased day by day. In fact, cancer or AIDS patients die of the fungal infection of their organs or blood rather than the disease itself. Furthermore, fungi that cause fungal infections have been progressively diversified, and it is expected that much more kinds of fungi will cause invasive infections.
Antifungal agents that are currently used in clinical practice are mostly azole-based compounds in addition to amphotericin B. However, such antifungal agents have the disadvantage of causing severe side effects when being used.
Commercially available antifungal agents have various disadvantages, including toxicity, a narrow spectrum of activity, and fungistatic rather than fungicidal nature. Some of these antifungal agents also show drug-drug interactions that make treatment very complex. In recent years, as fungal infection in immunosuppressive patients has frequently occurred and the population of these patients has increased steadily, there has been an increasing demand for new antifungal agents having broad-spectrum activity and excellent pharmacological properties.
Meanwhile, FK506 was isolated as a metabolite of Streptomyces tsukabaensis by the Fujisawa research group (Japan) in 1984. In 1989, a clinical trial using FK506 for liver transplantation was initiated. FK506 is 50-100 times stronger in efficacy than Cyclosporine A while it is comparable to Cyclosporine A in tex-ms of toxicity or side effects. Merck (USA) has conducted studies to modify the structure of FK506 in order to reduce the toxicity thereof, and the mechanism of action and functions of FK506 were considerably revealed during such studies.
Functionally, FK506 can be divided into three regions: the KFBP-binding domain, the calcineurin-binding domain, and the northwest region. The intermolecular interactions between FK506 and FKBP12 molecules are mostly hydrophobic, and only four intermolecular hydrogen bonds are formed between the two molecules. It is known that, as FK-506 and FKBP-12 bind more potently, they gain a greater affinity for calcineurin. Such increased affinity then leads to greater immunosuppressive activity. The northwest region of FK506 does not interact with FKBP12 or calcineurin.
FK506 has been used as therapeutic agents against organ or tissue transplantation rejection, graft-versus-host responses, atopic dermatitis, allergic contact dermatitis, lichen planus mucosae, and pyoderma gangrenosum. In recent years, other functions of FK506 have been found. For example, the literature [Sulaiman O A, et al., Exp Neurol 2002 May, 175(1): 127-37] describes that FK506 promotes the regeneration of peripheral nerve.
Korean Patent Application Publication No. 10-2004-0010919 (entitled “A method for inhibiting cellular aging using FK506 or a derivative thereof and a culture medium”) discloses a method of inhibiting cellular aging, extending cell life and increasing cell growth in culture by use of FK506 or a derivative thereof.
In addition, Korean Patent Application Publication No. 10-2005-0071491 (entitled: Use of tacrolimus derivatives combined with β2-agonists for the treatment of asthma”) discloses a new use of FK506 derivatives and β2-agonist for manufacturing a medicament for simultaneous, separate or sequential use for treating or preventing acute or chronic asthma.
However, the use of FK506 derivatives for treating a fungal infection caused by a fungus of the genus Cryptococcus or a fungus of the genus Candida has not yet been reported.